Pathophysiological role of guanylate-binding proteins in gastrointestinal diseases

Abstract

Guanylate-binding proteins (GBPs) are interferon-stimulated factors involved in the defense against cellular pathogens and inflammation. These proteins, particularly GBP-1, the most prominent member of the family, have been established as reliable markers of interferon-γ-activated cells in various diseases, including colorectal carcinoma (CRC) and inflammatory bowel diseases (IBDs). In CRC, GBP-1 expression is associated with a Th1-dominated angiostatic micromilieu and is correlated with a better outcome. Inhibition of tumor growth by GBP-1 is the result of its strong anti-angiogenic activity as well as its direct anti-tumorigenic effect on tumor cells. In IBD, GBP-1 mediates the anti-proliferative effects of interferon-γ on intestinal epithelial cells. In addition, it plays a protective role on the mucosa by preventing cell apoptosis, by inhibiting angiogenesis and by regulating the T-cell receptor signaling. These functions rely to a large extent on the ability of GBP-1 to interact with and remodel the actin cytoskeleton.

Keywords: Colorectal carcinoma; Guanylate-binding proteins; Inflammatory bowel diseases; Interferon.

Figure 1

Structure-function relationships of guanylate-binding protein-1. The guanylate binding protein-1 can be roughly divided into two domains: a compact globular domain carrying the GTPase activity at the N-terminus (blue) and a long helical domain comprised of α-helices at the C-terminus (grey), which are responsible for different protein functions.

Figure 2

Role of guanylate-binding protein-1 in colorectal carcinoma and inflammatory bowel diseases. In colorectal carcinoma (CRC), guanylate-binding protein (GBP)-1 expression is associated with a Th1-dominated micromileu and results in an angiostatic vasculature. In CRC tumor cells, expression of GBP-1 induces an anti-tumorigenic phenotype. Absence of expression in tumor cells in a GBP-1-positive context indicates a mechanism of resistance. In T-cells, GBP-1 participates in the modulation of the T-cell receptor signaling pathway. In inflammatory bowel disease (IBD), GBP-1 expression is elevated in active disease and inhibits the proliferation of intestinal epithelial cells, thereby exerting a protective effect against the loss of barrier function and apoptosis. Here again, GBP-1 is associated with angiostasis and T-cell regulation. INF: Interferon; IL: Interleukin.